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  • Title: Neuropeptide Y and the nonpeptide antagonist BIBP 3226 share an overlapping binding site at the human Y1 receptor.
    Author: Sautel M, Rudolf K, Wittneben H, Herzog H, Martinez R, Munoz M, Eberlein W, Engel W, Walker P, Beck-Sickinger AG.
    Journal: Mol Pharmacol; 1996 Aug; 50(2):285-92. PubMed ID: 8700135.
    Abstract:
    Neuropeptide Y (NPY) is a 36-amino acid peptide that exhibits actions on the cardiovascular system and the central nervous system. NPY can regulate blood pressure, psychomotor function, anxiety, food intake, and endocrine secretions. BIBP 3226, the first potent and selective nonpeptide antagonist at the NPY Y1 receptor, was designed by mimicking the carboxyl-terminal structure of NPY. We investigated the interaction of NPY and BIBP 3226 with the human Y1 receptor at the molecular level. Alanine mutants at positions Y100, D104, W288, and H298 of the human Y1 receptor showed no or significantly reduced binding for NPY but were not affected in their ability to bind BIBP 3226. Receptors with alanine mutations at positions W163, F173, Q219, N283, F286, and D287 showed reduced binding for both NPY and BIBP 3226. Mutations at other positions were tested (H105, S170, L174, V178, D200, D205, S206, H207, S210, T212, T280, T284, N289, H290, and Q291) and did not affect the binding of NPY or BIBP 3226. The human Y1 receptor mutant Y211A showed no affinity for BIBP 3226 but retained wild-type affinity for NPY. Based on these experimental results, a detailed model for the interaction of BIBP 3226 with the human Y1 receptor was developed using a Y1 receptor model and a three-dimensional model of BIBP 3226. The experimental results, supported by modeling studies, clearly suggest that the native ligand (NPY) and the antagonist (BIBP 3226) share an overlapping binding site.
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